With this the only possible route of qualifying for next year's UEFA Champions League for Jürgen Klopp's side, confirmed by their second-string's comfortable defeat to Swansea City at the weekend, the match represents more than just these 90 minutes.
Sitting at Europe's top-table woud not only allow Liverpool to restore some of the pride and prestige of the club's glittering European reputation, but it would open up a world of possibilities for Klopp - particularly in terms of attracting bigger and better players to mould an improved team around for the future.
But it will be no easy task for them to get there. The Reds find themselves in quite the predicament, with Villarreal having proven themselves excellent at staying tight, organised and compact across the back and then counter-attacking with pace and precision.
That was exactly how their late first-leg winner came about, no more than six passes required to move the ball 70-yards up the pitch and release Denis Suárez through on goal, for him to square to López to open the scoring.
That goals means Liverpool are in danger of leaving themselves open on the break if they overcommit in the return tie - whilst they cannot afford to be too cautious given that they require at least one goal to take it to extra time, or two to take an aggregate lead and progress.
Villarreal's quality has been proven in La Liga all season and Marcelino's much-changed side's 2-0 win over Valencia on Sunday moved them six points clear of Athletic Club Bilbao in fourth-place, the country's final qualification spot for the Champions League.
With game-changing quality throughout their squad, they have the ability both to frustrate the Reds and obliterate them in equal measure, meaning Klopp will have to get his game plan practically perfect to outwit his opposite number.
Indeed, all the ingredients suggest it could be another one of those famous Anfield nights on L4. With Liverpool having progressed to the final on three of the five occasions in which they have lost the first-leg of a semi-final away from home, they are left requiring another against-the-odds comeback to confirm a trip to Switzerland later this month.
Emre Can could make a remarkable recovery from an ankle ligament injury sustained in the previous round at home to Borussia Dortmund to feature.
The German midfielder has missed Liverpool's last five matches with initial assessments indicating he would be out for at least 4-6 weeks, but he could make a return inside three.
Can was back in full training earlier this week after recovering quicker than expected and is in contention to feature, potentially handing Klopp a huge boost if the medical team give the 22-year-old the green light to play.
Captain Jordan Henderson will not involved as he continues to recover from a knee ligament injury, whilst Divock Origi's ankle ligament problem looks likely to keep him out for the rest of the season.
Mamadou Sakho will be absent as he continues to serve a provisional suspension after testing positive for traces of an illegal substance, whilst several players who were rested for the weekend's defeat at Swansea City are expected to return.
Villarreal fly to Merseyside with no injury worries, after making 10 changes to the first-team against Valencia - striker Roberto Soldado the only one to keep his place in the line-up.
Léo Baptistão and Eric Bailly were the only injury worries, with the promising young centre-back suffering from discomfort in his hamstring in the closing stages of the first-leg and the Brazilian striker having spent time out with a thigh issue.
However, both have now made quick returns from their respective injuries and are likely to be in the 18-man matchday squad after being included in the provisional 22-man travelling party.
At Anfield: No meetings.
At El Madrigal: Villarreal - 1 wins, Draws - 0, Liverpool - 0 wins.
Overall: Liverpool - 0 wins, Draws - 0, Villarreal - 1 wins.
Last (and only) competitive meeting: Villarreal 1-0 Liverpool, Europa League semi-final first-leg, April 28th 2015.
Liverpool's record - Spanish opposition: W13, D10, L10 (W4, D6, L5 at Anfield).
Villarreal's record - English opposition: W4, D6, L4 (W1, D2, L3 in England).
Form in UEFA Europa League: WDDWL
Form in all competitions: WWDLL
Form in UEFA Europa League: WDWWW
Form in all competitions: LLDWW
This will be the first meeting between the two teams at Anfield.
Villarreal have only failed to score once away from home in Europe, recording 11 goals in six away games.
Marcelino's side are unbeaten in their last five away games in the Europa League, although only two have them have been wins.
Villarreal's 1-0 first-leg win was their 12th consecutive unbeaten match in the Europa League, having won nine games in that streak. It also ended Liverpool's 12-game undefeated run.
The Yellow Submarine have lost just four of their last 24 matches in all competitions, winning 11.
Before the first-leg of this tie, Villarreal were 10 matches without a win against Premier League opponents.
Liverpool have won all four of their last European matches at Anfield, becoming the only team to go unbeaten from the start of the Europa League group stages to the semi-finals.
Jürgen Klopp's charges have won five and drawn two of their last seven home games in all competitions, scoring 20 goals.
Liverpool have only lost 3 times in the second-leg of a semi-final in European competition, home or away. This is their 17th European semi-final, with the Reds hoping to reach a 12th final.
Of 16 semi-final games at home in Europe, Liverpool have won 12, drawn three and lost once - to Leeds United in 1971.
Villarreal's best ever campaign in this competition ended in the semi-finals, where they lost to Valencia in 2003-04 and Porto in 2010-11, both of whom went on to lift the trophy. They are the only team not to win it.
Three-times winners (1973, 1976, 2001) Liverpool haven't reached this stage of the competition since 2009-10, where they lost to Atletico Madrid. They were knocked out by Besiktas in last season's Round of 32, where they were also eliminated by Zenit St Petersburg in 2012-13.
Klopp's managerial record in 12 meetings wih Spanish opponents reads four wins, three draws and five losses - with Mainz, Dortmund and Liverpool winning their last four home games against La Liga teams.
Villarreal striker Cédric Bakambu has scored nine goals in the Europa League this term, behind only Aritz Aduriz of Athletic Bilbao with ten goals.
Liverpool goalkeeper Simon Mignolet and Villarreal defender Víctor Ruiz are the only players to have played every minute of their teams' campaigns, playing 1,170 minutes in total.
Man in the middle:
Hungarian football referee Viktor Kassai is the nominated match official, taking charge of his 17th Europa League fixture and his 91st UEFA match.
The 40-year-old, a full international referee for FIFA since 2003, officiated the 2011 UEFA Champions League final when Barcelona beat Manchester United 3-1, as well as participating in the 2010 World Cup and the 2012 European Championship. Kassai was even the referee for the final of the 2008 Olympic Games in Beijing.
Having been one of the selected referees for the 2016 Euros in France this summer, Kassai is one of the most high-profile referees in the game and was the man in the middle for Liverpool's 1-0 defeat away at Real Madrid in last season's Champions League group stages. However, he has never been the referee for a match involving Villarreal.